Drug‐Coated Balloons in Coronary Artery Disease: Engineering, Pharmacology, and the Mechanisms Behind Angiographic Outcomes

Drug-coated balloon (DCB) angioplasty represents a unique drug-delivery paradigm in which all therapeutic efficacy depends on the first seconds of device-tissue interaction. Unlike drug-eluting stents (DES), DCBs must achieve meaningful drug transfer, penetration, and retention during a single, brief inflation. This review provides a mechanistic, bench-to-bedside framework linking drug physicochemistry, excipient chemistry, coating engineering, balloon mechanics, and tissue pharmacokinetics to angiographic and clinical outcomes. Paclitaxel-based DCBs consistently outperform sirolimus-coated platforms in early drug uptake, intracellular retention, transmural distribution, and late lumen loss. These advantages derive from paclitaxel's extreme lipophilicity, particulate deposition, and high-affinity microtubule binding, which enable durable antiproliferative activity despite modest absolute transfer. Sirolimus, by contrast, requires an engineered delivery system-crystalline matrices, PLGA micro-reservoirs, nanoparticle carriers, or pressure-driven infusion-to compensate for its lower membrane permeability and reversible intracellular binding. Integrating preclinical modeling, coating-stability studies, optical coherence tomography (OCT) remodeling signatures, randomized trials, and recent meta-analyses, this review demonstrates that DCB therapy is not a drug-class effect: technology, not drug load, determines biological behavior. Early transfer efficiency, tissue retention kinetics, depth of penetration, and platform-specific dissection response fully explain the divergent angiographic patterns observed across devices. Understanding these mechanistic principles is essential for rational device selection and for guiding the next generation of DCB technologies capable of achieving consistent and durable clinical performance.